180: Antifungal Therapy

Question 1

What are the two available groups of antifungals?

Answer 1

• polyene antibiotics
• azole derivates

Question 2

What polyene antibiotic is used to treat systemic mycoses?

Answer 2

amphotericin B (AMB)
or lipid-complexed AMB

Question 3

How is amphotericin produced?

Answer 3

by Steptomyces nodosus

Question 4

How is the bioavailability of amphotericin B?

Answer 4

poor, requires parenteral administration

Question 5

How does amphotericin distribute in the body?

Answer 5

• protein bound
• low volume of distribution
• poor CNS penetration

Question 6

How does amphotericin kill fungal cells?

Answer 6

binds to ergosterol in fungal cell membranes –> increases membrane permeability and causes cell death

Question 7

What toxicity does amphotericin cause and how?

Answer 7

nephrotoxicity
* binds to cholesterol in the proximal tubular cells –> causes renal vasoconstriction and renal tubular acidosis

Question 8

What is the dosing protocol for amphotericin B?

Answer 8

• intermittent administration until a cumulative dosage has been achieved
• interruption of therapy in the event of azotemia

Question 9

How do you administer amphotericin B?

Answer 9

diluted in 5% dextrose and over 1-5 hours IV to reduce nephrotoxicity

Question 10

How do you monitor a patient for nephrotoxicity when undergoing amphotericin B treatment?

Answer 10

Before every dose BUN and urine sediment should be evaluated
* alter treatment regiments if tubular casts appear in urine sediment*
* if BUN exceeds 50 mg/dL discontinue treatment until azotemia resolves

*(earlier indicator than azotemia)

Question 11

How do azole antifungals act against fungal cells?

Answer 11

inhibit the fungal P-450 enzyme necessary for development of ergosterol in fungal cell walls –> increased fungal cell permeability –> cell death

Question 12

What are the classes of azoles and their antifungals?

Answer 12

triazoles:
* itraconazole
* fluconazole
* voriconazole
* pasoconazole
imidazoles:
* ketoconazole
* clotrimazole
* eniconazole
* miconazole

Question 13

What are the main differences between triazoles and imidazoles?

Answer 13

triazoles:
* less effect on mammal sterol synthesis
* longer elimination times
imidazoles:
* more endocrine adverse effects
* greater effects on mammal sterol synthesis

Question 14

Which one has best blood-brain penetration:
ketoconazole, fluconazole, or itraconazole?

Answer 14

Fluconazole

Question 15

What drugs may lead to higher plasma drug concentrations of azoles?

Answer 15

drugs metabolized by hepatic P-450

Question 16

What are adverse effects of ketoconazole therapy?

Answer 16

• GI upset
• induction of mammalial P-450 enzyem leading to elevation of ALT,AST, ALKP –> clinical hepatitis including fatalities has been reported

Question 17

Which one is more hepatotoxic and why?

Answer 17

Ketoconazole
itraconazole more selectively inhibits fungal P-450 enzymes than mammalian ones –> limits its hepatotoxicity

Question 18

What adverse effect is specific to the azole itraconazole?

Answer 18

cutaneous reactions consisting of localized ulcerative dermatitis andvasculitis
resolve following discontinuation of therapy

Question 19

What arethe benefits of Fluconazole over Ketoconazole?

Answer 19

• more soluble –> greater BBB penetration, more consistent oral absorption on empty stomac*
• more potent
• less risks of metabolic adverse effects

*good for anorexic animals or CNS involvement

Question 20

What is the treatment of choice for Blastomycosis?

Answer 20

Azoles
* similar response and occurence rates to amphotericin B but safer and more convenient administration

Fluconazole more cost effective than itraconazole

Question 21

What is the treatment of choice for Histoplasmosis?

Answer 21

Azoles
* itraconazole most widely studied treatment for histoplasmosis in cats and dogs
* however, GI absorption not reliable in GI histoplasmosis or disseminated histoplasmosis
* consider fluconazole for better absorption and in animals with CNS involvement

GI histoplasmosis or severe disseminated disease
* parenteral amphotericin B combined with itraconazole or high dose itraconazole

Question 22

How long should you treat an animal for Histoplasmosis?

Answer 22

• for at least 60 days OR
• until 1 month following resolution of clinical signs

Question 23

How long should you treat Coccidioidomycosis

Answer 23

For at least 3-6 months beyond resoltution of clinical signs

Question 24

What is the treatment of choice for coccidioidomycosis?

Answer 24

azoles
amphotericin B is indicated in animals with signficicant adverse ffects to azoles

Question 25

What is the treatment of choice for Cryptococcisis?

Answer 25

Azoles
* preferentially fluconazole in CNS, eye, or uurinary tract involvement

Question 26

How long are antifungals usually administered to treat cryptococcosis?

Answer 26

8-10 months
discontinue 1 month after resolution of clinical signs and decrease in antigen titer